US4973469A - Drug delivery system - Google Patents

Drug delivery system Download PDF

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Publication number
US4973469A
US4973469A US07/395,184 US39518489A US4973469A US 4973469 A US4973469 A US 4973469A US 39518489 A US39518489 A US 39518489A US 4973469 A US4973469 A US 4973469A
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Prior art keywords
controlled release
cross
release formulation
weight
formulation according
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US07/395,184
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English (en)
Inventor
Seamus Mulligan
Randall T. Sparks
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Elan Pharma International Ltd
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Elan Corp PLC
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets

Definitions

  • This invention relates to a method for the manufacture of adsorbates for use in drug delivery systems and to the adsorbates and drug formulations thereby obtained.
  • an active substance it is frequently desirable to delay the release of an active substance from a pharmaceutical formulation in vivo. For example, it may be desirable to delay release of the active substance within the body so that the active substance is released at a particular target site.
  • Various coated tablets are available which are resistant to gastric juices but which are readily soluble in the higher pH environment of the small intestine.
  • Various controlled absorption pharmaceutical formulations are also available which have a particular dissolution pattern, resulting in a controlled absorption of the active substance and, therefore, more effective medication.
  • compositions based on an absorbate of a drug within a cross-linked polymer are also known.
  • solid, rapidly absorbable medicament formulations comprising a dihydropyridine, polyvinylpyrrolidone with an average molecular weight of 15,000 to 50,000 and cross-linked insoluble polyvinylpyrrolidone are known from EP-A-No. 0 167 909.
  • the invention provides a controlled release formulation comprising an adsorbate of a mixture of 1 part by weight of a pharmaceutically useful active ingredient and from 0.1 to 10 parts by weight of an inactive substance adsorbed on a cross-linked polymer in a ratio of 1 part by weight of said mixture to 0.5-20 parts by weight of cross-linked polymer, said inactive substance being selected to modify the dissolution of the active drug from the cross-linked polymer in vivo, with the proviso that the active ingredient is not a dihydropyridine when the inactive substance is polyvinylpyrrolidone with an average molecular weight in the range 15,000 to 50,000 and the cross-linked polymer is cross-linked polyvinylpyrrolidone.
  • the existence of the drug (active ingredient) in the pore spaces of the cross-linked polymer can be confirmed by x-ray diffraction studies.
  • the formation of the adsorbate results in an amorphous state which can be verified by x-ray diffraction and, in addition, differential scanning calorimetery.
  • the inactive substance is preferably present in the adsorbate in an amount of 0.5-3 parts by weight relative to 1 part by weight of the active ingredient. Furthermore, the formulation preferably contains 1 part by weight of said mixture relative to 1-10 parts by weight of cross-linked polymer.
  • the invention also provides a process for preparing a controlled release formulation as defined above, which comprises dissolving the active ingredient and the inactive substance in a common solvent, mixing the solution thereby obtained with a given quantity of the cross-linked polymer so as to permit adsorption of said active ingredient and said inactive substance to said cross-linked polymer and removing the solvent.
  • the solvent used is any -pharmaceutically suitable co-solvent for the active drug and the inactive substance.
  • the solvent is suitably selected from water, alcohols, ketones, halogenated aliphatic compounds, halogenated aromatic hydrocarbon compounds, aromatic hydrocarbon compounds and cyclic ethers or a mixture thereof.
  • Especially preferred solvents include water, hexane, heptane, methanol, ethanol, isopropyl alcohol, acetone, methylethyl ketone, methylisobutyl ketone, methylene chloride, chloroform, carbon tetrachloride, toluene, xylene and tetrahydrofuran.
  • the inactive substance is chosen to modify the dissolution of the active drug from the cross-linked polymer such that a water soluble inactive substance will serve to enhance the rate of active drug leaching from the cross-linked polymer. Conversely, a water insoluble material would serve to impede the rate of active ingredient leaching from the cross-linked polymer as will be appreciated by one skilled in the art.
  • the inactive substance is also chosen to modify the crystalline properties of the active ingredient both in the controlled release formulation as prepared and in vivo after administration of the formulation.
  • cross-linked polymer is cross-povidone (Polplasdone XL (GAF), Kollidon CL (BASF) Polplasdone XL and Kollidon CL are Trade Marks).
  • Others include cross-linked carboxymethylcellulose and cross-linked methylcellulose.
  • any drug, subject to the above proviso, is suitable for use as active ingredient in the formulation according to the present invention.
  • preferred drugs include ibuprofen, acylovir, 5-amino-salicyclic acid, dextromethorphan, propranolol, theophylline, methyldopa, pseudoephedrine, cimetidine, cephalexin, cephaclor, cephradine, naproxen, piroxicam, diclofenac, indomethacin, amoxycillin, pivampicillin, bacampicillin, dicloxacillin, erythromycin, lincomycin, co-dergocrine mesylate, doxycycline, dipyridamole, frusemide, triamterene, sulindac, nifedipine, nicardipine, 4-(2, 1, 3-bensoxadiasol-4-yl)-2, 6-dimethyl-1, 4-dihydro-3-isopropy
  • Especially preferred active ingredients include chlorpheniramine, diclofenac, theophylline, felodipine, nifedipine, nicardipine, nitrendipine, 4-(2, 1, 3-benzoxadiazol-4-yl)-2,6-dimethyl-1,4-dihydro-3-isopropyloxycarbonyl-pyridine-5-carboxylic acid methyl ester, co-dergocrine mesylate, oxendolone, azidothymidine (AZT) and spironolactone.
  • chlorpheniramine diclofenac
  • theophylline felodipine
  • nifedipine nicardipine
  • nitrendipine 4-(2, 1, 3-benzoxadiazol-4-yl)-2,6-dimethyl-1,4-dihydro-3-isopropyloxycarbonyl-pyridine-5-carboxylic acid methyl ester
  • inactive substance for use in controlling the dissolution of the adsorbed active drug according to the present invention is determined by the particular pharmacological properties desired.
  • a water insoluble inactive substance may be used to delay the release of a highly water soluble drug. Similar results could be obtained with a polymer of low porosity or a polymer which is only slightly permeable to water when such is used as the inactive substance.
  • inactive substances include inert polymers such as, for example, polyvinyl alcohol, polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, alkyl-celluloses such as methyl- and ethylcellulose, shellac, polymers sold under the trademark Eudragit, polyethylene glycol, sodium alginate, galactomannone or carboxypolymethylene or mixtures thereof.
  • inert polymers such as, for example, polyvinyl alcohol, polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, alkyl-celluloses such as methyl- and ethylcellulose, shellac, polymers sold under the trademark Eudragit, polyethylene glycol, sodium alginate, galactomannone or carboxypolymethylene or mixtures thereof.
  • Eudragit polymers are polymeric lacquer substances based on acrylates and/or methacrylates.
  • suitable inactive substances for use in the system according to the invention include sugars and many organic acids, such as adipic acid, ascorbic acid, citric acid, fumaric acid, maleic acid, succinic acid or tartaric acid.
  • inactive substance is generally made by reference to the solubility of the active substance and will usually have its own solubility inversely proportional to that of the active drug. Therefore, water insoluble, polymeric materials have use in conjunction with highly water-soluble active drugs as will be appreciated by one skilled in the art.
  • the invention also provides a controlled drug delivery system comprising a sustained release formulation as defined above, suitably granulated and blended with a polymer or mixture of polymers which gels in the presence of water, and optionally other ingredients.
  • the blend thereby obtained can be tabletted or encapsulated according to conventional methods, thereby yielding a long acting controlled release matrix system which also exhibits improved drug absorption.
  • Suitable polymers for blending with the controlled release formulation for subsequent tabletting or encapsulation are any one of the inert polymers cited above, which include both water soluble and water insoluble polymers.
  • An especially suitable group of polymers is the polymers sold under the Trade Mark Methocel.
  • a combination of a water soluble and a water insoluble polymer or a mixture of such polymers will be used, with the ratio of the water soluble to water insoluble polymer being varied to give the desired rate of release.
  • the permeabililty characteristic of the polymers/copolymers will be chosen to give the desired rate of release.
  • the adsorbates according to the present invention result in improved controlled drug delivery relative to known active drug adsorbates in cross-linked polymers, since the adsorbates according to the present invention yield a matrix system exhibiting both delayed or sustained release of active drug and improved absorption of said active drug in vivo when granulated and blended with pharmaceutically acceptable polymers.
  • Polyvinylpyrrolidone K-30 (Trade Mark) (2 kg) was dissolved in isopropylalcohol (10 kg). Nifedipine (1 kg) was then added to this solution and allowed to dissolve. The solution thereby obtained was then adsorbed onto cross-linked carboxymethylcellulose (4 kg) and the solvent evaporated. The resulting powder was then passed through an oscillating granulator to obtain a finer particle size. X-ray diffraction and differential scanning calorimetry studies were performed on the powder and demonstrated that the nifedipine was in an amorphous form. The powder (30%) was then tabletted with the following ingredients.
  • the ratio of nifedipine, polyvinylpyrrolidone and cross-linked carboxymethylcellulose may be altered within the limits which retain the amorphous nature of the drug. This also applies in the case of the subsequent Examples.
  • Methocel used may be Methocel K4M, K15M, K100M, or E, J, F grades depending on the release characteristics desired.
  • the gel forming polymer may be used in an amount of 3-50% with proportional changes in the percentage of adsorbate used. This also applies in the case of the subsequent Examples.
  • Polyvinylpyrrolidone K-30 (Trade Mark) (2 kg) was dissolved in isopropyl alcohol (10 kg). Nicardipine (1 kg) was then added to this solution and allowed to dissolve. The solution thereby obtained was then adsorbed onto a cross-linked carboxymethylcellulose (Croscarmellulose Trade Mark) (4 kg) and the solvent evaporated. The resulting powder was passed through an oscillating granulator to obtain a finer particle size. The powder (60%) was then tabletted with the following ingredients:
  • Example 1 The procedure of Example 1 was repeated except that the nifedipine was replaced by an equal amount (1 kg) of (4-(2,1,3-benzoxadiazol-4-yl)-2,6-dimethyl-1, 4-dihydro-3-isopropyloxycarbonyl-pyridine-5-carboxylic acid methyl ester to obtain tablets containing 10 mg mg of active ingredient.
  • Cross-povidone (4 kg) was added to the solution of spironolactone and polyvinylpyrrolidone so as to permit adsorption of the spironolactone and polyvinylpyrrolidone to the cross-povidone.
  • the solvent was then removed by heating.
  • the ability of the spironolactone to be dissolved out of the cross-povidone is enhanced by the ready solubility of the polyvinylpyrrolidone in water.
  • a given quantity (50%) of the adsorbate was granulated and blended with hydroxypropylmethylcellulose (50%). The blend thereby obtained was filled into soft gelatine capsules so as to obtain capsules containing (50 mg) of spironolactone.
  • Anhydrous theophylline (0.5 kg) and citric acid (1 kg) were dissolved in isopropyl alcohol (10 kg) and adsorbed on cross-povidone (2 kg) in the manner described in Example 1.
  • An adsorbate between anhydrous theophylline and citric acid was thereby obtained.
  • a given quantity (50%) of the adsorbate was granulated and blended with Eudragit RL (50%).
  • the blend was then filled into hard gelatine capsules (422 mg) so as to obtain capsules containing 300 mg of anhydrous theophylline.
  • the presence of the citric acid was found to enhance the solubility of the anhydrous theophylline at pH values in excess of 7 and was suitable for use in a long acting or sustained release drug formulation.
  • Chlorpheniramine maleate (0.5%) and ethylcellulose (1 kg) which is insoluble in water and thereby inactive in an aqueous environment were dissolved in isopropyl alcohol (10 kg) and adsorbed onto cross-povidone (2 kg) in the manner described in Example 1.
  • the powder (30%) was then tabletted with the following ingredients:
  • Example 7 The procedure employed was similar to that in Example 7 except that the amount of polyvinylpyrrolidone (K-30) used was 0.5 kg and also included was polyethylene glycol 6000 (1 kg).
  • Example 8 The procedure employed was similar to that in Example 8 except that the polyethylene glycol was replaced by methylcellulose (0.75 kg).
  • Example 7 The procedure employed was similar to that in Example 7 except that methylcellulose (0.75 kg) was used instead of polyvinylpyrrolidone 0.75 kg.
  • Example 7 The procedure used was similar to that employed in Example 7 except the polyvinylpyrrolidone (0.75 kg) was replaced by polyethylene glycol 6000 (1.5 kg).
  • Polyvinylpyrrolidone K-25 (Trade Mark) (0.50 kg) was dissolved in isopropyl alcohol (10 kg). Diclofenac (1 kg) was added to this solution and allowed to dissolve. The solution thereby obtained was then adsorbed onto cross-linked polyvinylpyrrolidone (2.5 kg) and the solvent evaporated. The resulting powder (60%) was treated as in Example 1 and tabletted with the following ingredients:
  • Methocel A4M (Trade Mark) (0.15 kg) was dissolved in dichloromethane (10 kg). Oxendolone (1 kg) was added to the solution and dissolved. The resulting solution was adsorbed onto cross-povidone (4 kg) and treated as per Example 1.
  • the resulting powder (80%) was tabletted with the following ingredients:
  • Example 1 was repeated except the nifedipine formulation (50%) was tabletted with the following ingredients.
  • Example 2 was repeated except the nicardipine formulation (50%) was tabletted with the following ingredients:
  • Example 6 was repeated except the chlorpheniramine maleate formulation (40%) was tabletted with the following ingredients.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
US07/395,184 1986-02-03 1989-08-17 Drug delivery system Expired - Lifetime US4973469A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IE30686A IE63321B1 (en) 1986-02-03 1986-02-03 Drug delivery system
IE306/86 1987-01-09

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US07009754 Continuation 1987-02-02

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US07/395,670 Expired - Lifetime US5128142A (en) 1986-02-03 1989-08-17 Sustained release drug delivery system
US07/395,184 Expired - Lifetime US4973469A (en) 1986-02-03 1989-08-17 Drug delivery system

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US (2) US5128142A (de)
EP (1) EP0232155B1 (de)
JP (1) JP2527432B2 (de)
AU (1) AU598514B2 (de)
CA (1) CA1288344C (de)
DE (1) DE3750619T2 (de)
DK (1) DK173082B1 (de)
ES (1) ES2060593T3 (de)
IE (1) IE63321B1 (de)
NZ (1) NZ219139A (de)
PH (1) PH24331A (de)
ZA (1) ZA87737B (de)

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DK52787A (da) 1987-08-04
CA1288344C (en) 1991-09-03
AU598514B2 (en) 1990-06-28
IE63321B1 (en) 1995-04-05
DK52787D0 (da) 1987-02-02
AU6820687A (en) 1987-08-06
DE3750619T2 (de) 1995-04-20
JPS62195322A (ja) 1987-08-28
DE3750619D1 (de) 1994-11-10
EP0232155A2 (de) 1987-08-12
US5128142A (en) 1992-07-07
EP0232155A3 (en) 1988-09-28
ES2060593T3 (es) 1994-12-01
ZA87737B (en) 1987-09-30
JP2527432B2 (ja) 1996-08-21
NZ219139A (en) 1989-02-24
EP0232155B1 (de) 1994-10-05
PH24331A (en) 1990-05-29
IE860306L (en) 1987-08-03
DK173082B1 (da) 1999-12-27

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